Peripheral neuropathies are among the most prevalent neurologic diseases. Because of the capacity of peripheral nerves to regenerate and repair, they are potentially among the most treatable. The projects in this proposal address fundamental issues in the pathogenesis of peripheral nerve disease. Project I examines the response of neuronal cell bodies to transection of the axon, focusing on the molecular biologic mechanisms resulting in reordered cytoskeletal protein synthesis and the nature of the signals initiating the axon reaction. Project II will examine the role of the 200 kd neurofilament protein in neuronal form and function, utilizing DNA transfection to determine assembly properties and transgenic mice with mutant NF-H genes. Taken together Projects I and II will extend our understanding of the role of neurofilaments in the neuron, and provide new insights into regenerative responses. Project III will study the mechanisms of myelin formation and maintenance, including the routes by which Po protein reaches the myelin sheath and the nature of the transport membrane systems and the endocytic pathways within the Schwann cell. Project IV will examine the cellular interactions in Wallerian degeneration distal to axotomy. The roles of macrophages in initiating the early axonal breakdown, in influencing Schwann cell responses, and in clearing myelin will be examined, and contrasted with models of prolonged axonal survival when macrophage responses are blocked. Project V will apply approaches and questions from the experimental studies in Projects I-IV to the study of human nerve biopsies. The results of these studies will provide new insights into normal cellular function in the peripheral nervous system and the pathogenesis of peripheral nerve disease.